Methamphetamine (METH) is a powerful psychostimulant drug that can produce dopamine (DA) neuronal degeneration in rodents, nonhuman primates and, possibly, humans. The mechanism underlying METH-induced DA neurotoxicity has yet to be identified. However, recent findings, detailed in the preliminary results section, indicate that gene expression is crucial for the expression of METH-induced DA neurotoxicity. The broad, long-term goal of this project is to identify specific genes or gene clusters that play a key role in early phases of METH-induced DA neurotoxicity. To this end, this research will use microarray technology, in conjunction with an experimental approach designed to facilitate recognition of relevant gene expression patterns, to identify arrays of gene expression uniquely associated early, active phases of METH-induced DA neurotoxicity. Four specific aims will be pursued. First, the time-course and pattern of gene expression during early phases of METH-induced DA neurotoxicity will be defined in selected mouse brain regions, the substantia nigra/ventral tegmental area and striatum. Second, the effects of pharmacological and environmental strategies known to block or enhance METH-induced DA neurotoxicity will be tested, with the expectation that such treatments will influence expression of gene product ensembles in a manner that will make it possible to identify gene expression patterns of interest. Third, the effects of neurotoxins with similar mechanisms of neurotoxic action as METH (amphetamine and methcathinone) will be evaluated, with the intent of further implicating certain gene expression patterns in METH neurotoxicity. Finally, the effect of METH neurotoxicity on gene expression patterns in DA transporter (DAT) knock-out (KO) and DAT overexpressor mice will be determined, again with the intent of identifying genes critical for the development of METH-induced DA neurotoxicity. Thus, by combining strengths of microarray technology with certain features of METH neurotoxicity (a well defined time- course, regional specificity, neuronal selectivity, drug specificity and susceptibility to blockade and enhancement), this research seeks to identify patterns of gene expression directly involved in early, active phases of METH-induced DA neurotoxicity. In the long-term, results from these studies may provide insight not only into molecular mechanisms of METH neurotoxicity, but also gene expression patterns involved in the pathogenesis of DA neuronal degeneration in Parkinson's disease and other neurodegenerative disorders involving DA neurons in humans.